Synribo Clears FDA Hurdle, Gains Nod in CML Patients

By Jennifer BoggsManaging Editor

Three years after a new drug application was first submitted for leukemia drug omacetaxine mepesuccinate, during which the product moved twice into different hands via M&A transactions, the FDA granted a long-awaited nod Friday.

Branded Synribo, the drug is approved for treating adults with chronic myelogenous leukemia (CML), a blood and bone marrow disease, specifically those whose disease has progressed following treatment from at least two tyrosine kinase inhibitors (TKIs) such as Gleevec (imatinib, Novartis AG).

Synribo, which is designed to block certain proteins that promote development of cancer cells, will be marketed by Teva Pharmaceutical Industries Ltd. It was acquired in the Jerusalem-based big pharma's $6.8 billion acquisition of Cephalon Inc. in 2011 – barely more than a month after Frazer, Pa.-based Cephalon agreed to pick it up via a $231 million buyout of Australian firm ChemGenex Pharmaceuticals Ltd. – and will add to Israeli firm's growing oncology pipeline. (See BioWorld Today, May 3, 2011.)

Over the past few years, Teva has sunk considerable investment in the oncology arena. In addition to its Cephalon buy – in which it outbid Canadian specialty pharma firm Valeant Pharmaceuticals International Inc. – it has picked up rights to Phase III-stage prostate cancer candidate custirsen in a partnership with OncoGenex Pharmaceuticals Inc. and gained a substantial stake in privately held CureTech Ltd., which boasts among its pipeline a diffuse large B-cell lymphoma candidate that yielded positive data in a Phase II trial. (See BioWorld Today, Dec. 22, 2009, and Sept. 14, 2011.)

According to the National Institutes of Health, about 5,430 people will be diagnosed with CML in 2012.

"The majority of the patients will do well [on TKIs] and the majority of them will eventually become resistant or intolerant to those TKIs," Brown told BioWorld Today. Those patients then are forced to fall back on less effective treatment options, so Synribo could become an important drug for continued treatment of the chronic disease.

With its approval, Synribo became the second drug in as many months to gain approval in CML. Pfizer Inc.'s Bosulif (bosutinib, a Bcr-Abl inhibitor, was cleared for patients with chronic, accelerated or blast phase Philadelphia chromosome-positive CML who are resistant to or who cannot tolerate other therapies. And both Teva's and Pfizer's drugs face a potential threat from Ariad Pharmaceuticals Inc.'s Bcr-Abl inhibitor ponatinib, which was recently granted priority review, with a PDUFA date of March 27, 2013.

RBC Capital Markets analyst Michael Yee said he sees Synribo offering little in the way of competition to ponatinib. "Bottom line is the efficacy and safety profile are quite inferior" to ponatinib. He pointed to major cytogenetic response in clinical trials for both compounds, which showed a 25 percent response for Synribo vs. a 41 percent to 65 percent for ponatinib. The major hematologic response was 14 percent for Synribo vs. 50 percent to 64 percent for ponatinib, Yee said.

"In addition, Synribo has up to double or triple the rates of thrombocytopenia, neutropenia and anemia," he noted in a research report.

But trying to compare data from both programs on a head-to-head basis is tricky. And Synribo's mechanism, though not completely elucidated, is different from that of ponatinib or Bosulif. A protein synthesis inhibitor, the drug is believed to act independently of direct Bcr-Abl binding to decrease protein levels of Brc-Abl oncoprotein. It also appears to affect short-lived anti-apoptotic protein McL-1 , allowing "leukemia cells to go through the process of cell death," Brown said.

How competition among the three drugs might shake out in the marketplace remains to be seen.

"We don't quite know yet until physicians start to use the drugs," Brown added. But "it's good news for patients to have different choices."

Designed initially to be injected subcutaneously twice a day for 14 consecutive days over a 28-day cycle, Synribo was approved under the FDA's accelerated approval program. Full approval is anticipated following the submission of more mature data from the pivotal analysis, Teva said.

Synribo, previously called Omapro in the hands of ChemGenex, went before the FDA initially in 2009, with the Melbourne, Australia-based biotech seeking approval in patients whose disease had progressed following Gleevec treatment and who tested positive for the T3151 genetic mutation. But in early 2010, the FDA's Oncologic Drugs Advisory Committee voted 7-1 calling for a companion diagnostic to identify patients with that mutation and an official FDA rejection followed. (See BioWorld Today, March 23, 2010.)

ChemGenex resubmitted the new drug application a few months later, seeking approval in all CML patients, regardless of genetic mutation, based on combined data from two pivotal studies. (See BioWorld Today, July 15, 2010.)

Beyond CML, Teva is "looking at additional indications" for Synribo, Brown said, though the firm hasn't disclosed any specific development plans as yet.